We previously reported that sodium excretion is significantly correlated to the excretion of nitrate/nitrite (metabolites of nitric oxide) in normotensive young adults. This association of the nitric oxide pathway with sodium excretion in humans led us to probe the mechanisms of how this mediator acts in the physiological response to changes in sodium intake in animal models. It was previously shown that the inner medullary collecting duct has the highest nitric oxide synthase (NOS) activity in the rat kidney. All three NOS isoforms are expressed in the collecting duct. Loss of functional NOS1 through pharmacological inhibition in rats delays the excretion of sodium and blunts nitrite/nitrate excretion following an acute salt challenge. Since the final control of sodium excretion occurs in the collecting duct, we have recently created collecting duct specific NOS1 knockout (CD NOS1 KO) mice. These mice were generated by the cre-lox technology in which the floxed exon 6 NOS1 mouse was mated with the aquaporin 2-cre mouse resulting in a selective knockout of NOS1 in the renal collecting duct tubules. Our preliminary data indicates that the CD NOS1 KO mice are hypertensive when compared to the control mice. The first aim of this 2 year proposal is to test the hypothesis that the CD NOS1 KO mice will exhibit a salt-sensitive hypertensive phenotype. We also predict that the pressure-dependent natriuresis and diuresis is dysfunctional in the CD NOS1 KO mice when compared to the control mice. Several NOS1 splice variants are known to be expressed in the kidney. Our preliminary data demonstrates that NOS1b is the predominant splice variant expressed in the mouse medulla. Commercially available NOS1a knockout mice do not have any blood pressure anomaly, yet the CD NOS1 KO mice display a hypertensive phenotype and do not express any NOS1 variants. Thus, the second aim of this 2 year proposal is to test the hypothesis that the NOS1b splice variant contributes to the control of sodium reabsorption in the collecting duct.